A L68Q variant cystatin C forms the amyloid deposited in cerebral vessel walls of patients with hereditary cerebral hemorrhage with amyloidosis, Icelandic type. There are several indications that cystatin C also has a pathogenic role in Alzheimer's disease (AD), in cerebral amyloid angiopathy and in cerebral hemorrhage. A) Cystatin C colocalizes with amyloid beta in amyloid deposits in the brains of AD patients. The risk of cerebral hemorrhage increases in AD patients when high levels of cystatin C are present in cerebrovascular amyloid beta deposits. B) Cystatin C binds amyloid beta and its precursor and affects amyloid precursor protein processing. C) Both proteins accumulate in pyramidal neurons within the cerebral cortex. D) Recent genetic data suggest that the human cystatin C gene is a recessive risk gene for late-onset AD. We have generated lines of transgenic mice designed to provide disease models for cystatin C-cerebral amyloid angiopathy. High transgene expression was observed in the brain and plasma of these mice. Several aging transgenic mice overexpressing wild type or L68Q variant human cystatin C exhibited gross- or micro-hemorrhages but fibrillar amyloid deposits were not detectable in the brains of these mice. We hypothesize that accumulation of nonfibrillar cystatin C may contribute to hemorrhagic strokes. We propose to: 1) Characterize these transgenic mice, including: a) determination of cystatin C levels in the brains and peripheral tissues of young, mature, and aged mice; b) perform standard necropsies on a similar panel of mice, including immunostaining for cystatin C and amyloid deposition; c) seek evidence of macro- or micro-hemorrhages using appropriate staining techniques; 2) Study the mechanism by which high concentration of cystatin C causes hemorrhages: test the possibilities that cystatin C accumulation is toxic to vessel walls, alters coagulation and/or complement pathways, or both; and 3) Study the effect of cystatin C on amyloid beta deposition and cerebral hemorrhage in mice overexpressing human amyloid precursor protein, crossbred with cystatin C transgenic mice. The proposed animal models are crucial for understanding the etiology of cerebral amyloid angiopathy and hemorrhage and for the development of rational therapeutic interventions.